WO2018054304A1 - Furoquinolinedione compound and medicinal use thereof - Google Patents

Abstract

A furoquinolinedione compound represented by formula (I), a prodrug, a stereoisomer, or a pharmaceutically-acceptable salt thereof, a pharmaceutical composition thereof, a preparation method therefor and a medicinal use thereof.

Description

Furan quinolinedione compounds and their medical use Technical field

The invention belongs to the field of medicinal chemistry, and in particular relates to a furanoquinolinedione compound and a medical use thereof.

Background technique

STAT3 is an important member of the Signal Transducer and Activator of Transcription (STAT) family. STAT3 has a wide range of functions that regulate gene expression associated with cell cycle, survival, and immune response, and is closely associated with the progression and progression of multiple tumors. Phosphorylation of two important sites of STAT3 is involved in STAT3 activation, namely tyrosine at position 705 and serine at position 727. Various tyrosine kinase entities (such as EGFR, VEGFR, and PDGF), non-tyrosine kinases (such as Arc and Abl), and cytokine receptors involved in JAK activation activate STAT3 705 tyrosine ( Tyr705) phosphorylation. The activation of various serine kinases (e.g., MAPK, ERK, JNK, PKC, and mTOR) activates STAT3 727 locus serine (Ser727) (Kamran MZ et al. BioMed Res Intern 2013 Article ID 421821). Phosphorylated STAT3 forms a dimer that is transferred into the nucleus to become an activated transcription factor that binds to the promoter region of its target gene, regulating downstream and anti-apoptotic, angiogenic, invasive, and migration-related gene expression. The constitutive activation of STAT3 in approximately 70% of human solid tumors. (Steffanie L et al. ACS Chem Biol. 11: 308-318, 2016; Yu H. et al. Nat Rev Cancer 14, 736-746, 2014).

Recent studies have found that STAT3 is closely related to the maintenance of tumor stem cell pluripotency (Wei W. et al. Stem Cells 32: 2571-2582, 2014; Marotta LLC. J Clin Invest. 121: 2723-2735, 2011).

STAT3 is an important target for antineoplastic agents. Multiple STAT3 inhibitors including OPB-51602, AZD9150, OPB-31121, WP1066 and BBI608 have entered the clinical research phase. BBI608 (Napabucasin) is a pluripotent inhibitor of cancer cells with STAT3 inhibitory activity. It can effectively inhibit the self-renewal of highly multifunctional cancer cells by down-regulating STAT3-driven stem cell gene expression and cancer stem cell performance. In tumor models, tumor metastasis and recurrence can be significantly inhibited (LiY., et al. PNAS 112: 1839-1844, 2015).

Summary of the invention

The inventors have found through extensive studies that a compound represented by the formula (I) has STAT3 inhibitory activity; for example, it is capable of inhibiting the expression level of STAT3 in various tumor cells; for example, it can inhibit phosphorylation of STAT3. Inhibition of STAT3 activation (eg, phosphorylation of tyrosine at position 7053; for example, phosphorylation of serine at position 7273); thus, the compound acts as a STAT3 inhibitor. For example, the compounds can be used to prevent or treat diseases associated with STAT3 (eg, tumors).

Further, the compound of the formula (I), a prodrug thereof, a stereoisomer or a pharmaceutically acceptable salt thereof inhibits proliferation of tumor cells, for example, inhibits proliferation of cancer cells of colon cancer, breast cancer, colon cancer and lung cancer. The compound of the formula (I), a prodrug, a stereoisomer or a pharmaceutically acceptable salt thereof of the present invention can be used for the preparation of a medicament for preventing and/or treating a tumor such as colon cancer, breast cancer, colon cancer, lung cancer.

Accordingly, one aspect of the application relates to a compound of formula (I), a prodrug thereof, a stereoisomer or a pharmaceutically acceptable salt thereof,

among them,

The A, B, D and E atoms are each independently selected from the group consisting of a C atom and an N atom, and at least one (for example 1, 2, 3 or 4) is an N atom;

R _{1 is} selected from the group consisting of hydrogen, halogen, nitro, cyano, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, 6-14 a aryl group and a 5-14 membered heteroaryl group; wherein the C ₁ -C ₆ alkyl group, a C ₁ -C ₆ alkoxy group, a C ₂ -C ₆ alkenyl group, a C ₂ -C ₆ alkynyl group, The -14 membered aryl group and the 5-14 membered heteroaryl group are unsubstituted or substituted by one or more (e.g., 1, 2, 3 or 4) substituents selected from the group consisting of halogen, hydroxy, amino, cyano. , C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkylamino, C ₁ -C ₆ alkylthio and C ₁ -C ₆ alkyl Sulfonyl;

R _{2 is} selected from the group consisting of C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₆ cycloalkyl, 6-14 membered aryl and 5-14 membered heteroaryl a C ₁ -C ₆ alkyl group, a C ₂ -C ₆ alkenyl group, a C ₂ -C ₆ alkynyl group, a C ₃ -C ₆ cycloalkyl group, a C ₃ -C ₆ cycloalkylmethyl group, The 6-14 membered aryl group and the 5-14 membered heteroaryl group are unsubstituted or substituted by one or more (e.g., 1, 2, 3 or 4) substituents selected from the group consisting of halogen, hydroxy, amino, cyanide , C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkylamino, C ₁ -C ₆ alkane Thio group and C ₁ -C ₆ alkylsulfonyl group;

R _{3 is} selected from the group consisting of hydrogen, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl and C ₃ -C ₆ cycloalkyl; wherein said C ₁ -C ₆ alkyl , C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl and C ₃ -C ₆ cycloalkyl are unsubstituted or one or more (for example 1, 2, 3 or 4) are selected from the group consisting of Substituent substitution: halogen, hydroxy, amino, cyano, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkylamino, C ₁ -C ₆ alkylthio and C ₁ -C ₆ alkylsulfonyl.

In certain preferred embodiments of the present application, the A, B, D and E atoms are each independently selected from the group consisting of a C atom and an N atom, and one of A, B, D and E is an N atom; R _{1 is} selected from hydrogen. Halogen, nitro, cyano, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, aryl and heteroaryl, wherein said C ₁ -C ₆ alkyl, C ₁ -C ₆ The alkoxy, aryl and heteroaryl groups are unsubstituted or substituted by one or more (for example 1, 2, 3 or 4) substituents selected from the group consisting of halogen, hydroxy, amino and cyano; R ₂ Is C ₁ -C ₆ alkyl or aryl; R ₃ is hydrogen or C ₁ -C ₆ alkyl.

In certain preferred embodiments of the present application, R _{1 is} selected from the group consisting of hydrogen, halogen, nitro, cyano, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, 6-14 membered aryl, and 5 a -6 membered heteroaryl group; wherein the C ₁ -C ₆ alkyl group, the C ₁ -C ₆ alkoxy group, the 6-14 membered aryl group and the 5-6 membered heteroaryl group are unsubstituted or one or more (for example 1, 2, 3 or 4) substituted with a substituent selected from the group consisting of halogen, hydroxy, amino, cyano, C ₂ -C ₄ alkenyl, C ₂ -C ₄ alkynyl, C ₁ -C ₄ alkoxy, C ₁ -C ₄ alkylamino, C ₁ -C ₄ alkylthio and C ₁ -C ₄ alkylsulfonyl.

In certain preferred embodiments of the present application, R _{1 is} selected from the group consisting of hydrogen, halogen, nitro, cyano, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, phenyl, and 5-6 membered An aryl group; wherein the C ₁ -C ₆ alkyl group, C ₁ -C ₆ alkoxy group, phenyl group and 5-6 membered heteroaryl group are unsubstituted or one or more (eg 1, 2, 3) Or 4) substituents selected from the group consisting of halogen, hydroxy, amino and cyano.

In certain preferred embodiments of the present application, R _{1 is} selected from the group consisting of hydrogen, halogen, nitro, cyano, trifluoromethyl, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, phenyl, and a 5-6 membered heteroaryl group; wherein the 5-6 membered heteroaryl group is selected from the group consisting of furan, thiophene, pyrrole, pyrimidine, pyrazine, pyridazine and pyrimidine.

In certain preferred embodiments of the present application, R _{1 is} selected from the group consisting of hydrogen, halogen, nitro, cyano, trifluoromethyl, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, phenyl, Furan, thiophene, pyrrole, pyrimidine, pyrazine, pyridazine and pyrimidine.

In certain preferred embodiments of the present application, R ₁ is C ₁ -C ₆ alkyl.

In certain preferred embodiments of the present application, R ₁ is C ₁ -C ₄ alkyl.

In certain preferred embodiments of the present application, R ₁ is methyl.

In certain preferred embodiments of the present application, R ₁ is methyl or ethyl.

In certain preferred embodiments of the present application, R ₁ is methyl, ethyl or propyl.

In certain preferred embodiments of the present application, R _{1 is} selected from the group consisting of hydrogen, fluorine, chlorine, nitro, cyano, trifluoromethyl, methyl, ethyl, propyl, isopropyl, butyl, isobutyl Base, methoxy, ethoxy, phenyl, furan and thiophene.

In certain preferred embodiments of the present application, R _{1 is} selected from the group consisting of halogen, nitro, cyano, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, aryl, and heteroaryl; The C ₁ -C ₆ alkyl group, the C ₁ -C ₆ alkoxy group, the aryl group and the heteroaryl group are unsubstituted.

In certain preferred embodiments of the present application, R _{1 is} selected from the group consisting of halogen, nitro, cyano, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, phenyl, and 5-6 membered heteroaryl Wherein the C ₁ -C ₆ alkyl group, the C ₁ -C ₆ alkoxy group, the phenyl group and the 5-6 membered heteroaryl group are unsubstituted.

In certain preferred embodiments of the present application, R _{1 is} selected from the group consisting of halogen, nitro, cyano, trifluoromethyl, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, phenyl, furan, Thiophene, pyrrole, pyrimidine, pyrazine, pyridazine and pyrimidine.

In certain preferred embodiments of the present application, R _{1 is} selected from the group consisting of fluorine, chlorine, nitro, cyano, trifluoromethyl, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, Methoxy, ethoxy, phenyl, furan and thiophene.

In certain preferred embodiments of the present application, R ₂ is C ₁ -C ₆ alkyl or aryl; wherein the C ₁ -C ₆ alkyl and aryl are unsubstituted or one or more (eg, 1, 2, 3 or 4) substituted with a substituent selected from the group consisting of halogen, hydroxy, amino, cyano, C ₂ -C ₄ alkenyl, C ₂ -C ₄ alkynyl, C ₃ -C ₆ naphthenic a group, a C ₁ -C ₄ alkoxy group, a C ₁ -C ₄ alkylamino group, a C ₁ -C ₄ alkylthio group, and a C ₁ -C ₄ alkylsulfonyl group.

In certain preferred embodiments of the present application, R ₂ is C ₁ -C ₄ alkyl or phenyl.

In certain preferred embodiments of the present application, R _{2 is} selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and phenyl.

In certain preferred embodiments of the present application, R ₂ is C ₁ -C ₆ alkyl.

In certain preferred embodiments of the present application, R ₂ is C ₁ -C ₄ alkyl.

In certain preferred embodiments of the present application, R ₂ is methyl.

In certain preferred embodiments of the present application, R ₂ is methyl or ethyl.

In certain preferred embodiments of the present application, R ₂ is methyl, ethyl or propyl.

In certain preferred embodiments of the present application, R _{3 is} selected from hydrogen or C ₁ -C ₆ alkyl; wherein the C ₁ -C ₆ alkyl group is unsubstituted or one or more (eg 1, 2 , 3 or 4) substituents selected from the group consisting of halogen, hydroxy, amino, cyano, C ₂ -C ₄ alkenyl, C ₂ -C ₄ alkynyl, C ₁ -C ₄ alkoxy, C _{a 1-} C ₄ alkylamino group, a C ₁ -C ₄ alkylthio group and a C ₁ -C ₄ alkylsulfonyl group;

In certain preferred embodiments of the present application, R _{3 is} selected from the group consisting of hydrogen and C ₁ -C ₄ alkyl.

In certain preferred embodiments of the present application, R ₃ is hydrogen or methyl.

In certain preferred embodiments of the present application, R ₃ is hydrogen.

In certain preferred embodiments of the present application, R ₃ is methyl.

In certain preferred embodiments of the present application, the compound has the structure shown in formula (II):

Wherein R ₁ , R ₂ , R ₃ are as defined in the compounds of formula (I) herein.

In certain preferred embodiments of the present application, R ₁ in formula (II) is at the meta or para position of the N atom.

In certain preferred embodiments of the present application, R ₁ in formula (II) is in the meta position of the N atom.

In certain preferred embodiments of the present application, R ₁ in formula (II) is in the para position of the N atom.

In certain preferred embodiments of the present application, R ₁ in formula (II) is selected from the group consisting of hydrogen, methyl, ethyl, propyl, isopropyl, fluoro, chloro, bromo, nitro, cyano, methoxy. , furyl, thienyl and phenyl.

In certain preferred embodiments of the present application, R ₁ in formula (II) is selected from the group consisting of hydrogen, fluoro, chloro, nitro, cyano, methyl, ethyl, isopropyl, methoxy, phenyl, furan. And thiophene.

In certain preferred embodiments of the present application, R ₁ in formula (II) is selected from the group consisting of hydrogen, methyl, ethyl and furanyl.

In certain preferred embodiments of the present application, R ₁ in formula (II) is selected from the group consisting of methyl, ethyl, propyl, isopropyl, fluoro, chloro, bromo, nitro, cyano, methoxy, furan. , thiophene and phenyl.

In certain preferred embodiments of the present application, R ₁ in formula (II) is C ₁ -C ₆ alkyl.

In certain preferred embodiments of the present application, R ₁ in formula (II) is C ₁ -C ₄ alkyl.

In certain preferred embodiments of the present application, R ₁ in formula (II) is methyl.

In certain preferred embodiments of the present application, R ₁ in formula (II) is methyl, ethyl or propyl.

In certain preferred embodiments of the present application, R ₁ in formula (II) is methyl or ethyl.

In certain preferred embodiments of the present application, R ₂ in formula (II) is a C ₁ -C ₆ alkyl group.

In certain preferred embodiments of the present application, R ₂ in formula (II) is a C ₁ -C ₄ alkyl group.

In certain preferred embodiments of the present application, R ₂ in formula (II) is selected from the group consisting of methyl, ethyl, isopropyl, and phenyl.

In certain preferred embodiments of the present application, R ₂ in formula (II) is methyl.

In certain preferred embodiments of the present application, R ₂ in formula (II) is methyl or ethyl.

In certain preferred embodiments of the present application, R ₂ in formula (II) is methyl, ethyl or propyl.

In certain preferred embodiments of the present application, R ₃ in formula (II) is hydrogen or methyl.

In certain preferred embodiments of the present application, R ₃ in formula (II) is hydrogen.

In certain preferred embodiments of the present application, R ₃ in formula (II) is methyl.

In certain preferred embodiments of the present application, the compound has the structure shown in formula (III):

Wherein R ₁ , R ₂ , R ₃ are as defined in the compounds of formula (I) herein.

In certain preferred embodiments of the present application, R ₁ in formula (III) is at the meta or para position of the N atom.

In certain preferred embodiments of the present application, R ₁ in formula (III) is in the meta position of the N atom.

In certain preferred embodiments of the present application, R ₁ in formula (III) is in the para position of the N atom.

In certain preferred embodiments of the present application, R ₁ in formula (III) is selected from the group consisting of hydrogen, methyl, methoxy, fluoro, chloronitro and cyano.

In certain preferred embodiments of the present application, R ₁ in formula (III) is selected from the group consisting of hydrogen, fluoro, chloro, nitro, cyano, methyl, ethyl, isopropyl, methoxy, phenyl, furan. And thienyl.

In certain preferred embodiments of the present application, R ₁ in formula (III) is selected from the group consisting of fluorine, chlorine, nitro, cyano, methyl, ethyl, isopropyl, methoxy, phenyl, furanyl, and Thienyl.

In certain preferred embodiments of the present application, R ₁ in formula (III) is methyl or ethyl.

In certain preferred embodiments of the present application, R ₁ in formula (III) is hydrogen.

In certain preferred embodiments of the present application, R ₂ in formula (III) is selected from the group consisting of methyl, ethyl, isopropyl, and phenyl.

In certain preferred embodiments of the present application, R ₂ in formula (III) is methyl.

In certain preferred embodiments of the present application, R ₃ in formula (III) is hydrogen or methyl.

In certain preferred embodiments of the present application, R ₃ in formula (III) is hydrogen.

In certain preferred embodiments of the present application, the compound has the structure of formula (IV) or formula (V):

Wherein each substituent is as defined in the compound of formula (I) of the present application.

In certain preferred embodiments of the present application, R _{1 in} formula (IV) or formula (V) is hydrogen.

In certain preferred embodiments of the present application, R _{2 in} formula (IV) or formula (V) is methyl or phenyl.

In certain preferred embodiments of the present application, R _{2 in} formula (IV) or formula (V) is phenyl.

In certain preferred embodiments of the present application, R _{2 in} formula (IV) or formula (V) is methyl.

In certain preferred embodiments of the present application, R _{3 in} formula (IV) or formula (V) is hydrogen.

In certain preferred embodiments of the present application, the compound has the structure shown in formula (VI) or formula (VII):

among them,

R ₁ is a C ₁ -C ₆ alkyl group;

R ₂ is a C ₁ -C ₆ alkyl group.

In certain preferred embodiments of the present application, R ₁ in formula (VI) or formula (VII) is C ₁ -C ₄ alkyl.

In certain preferred embodiments of the present application, R ₁ in formula (VI) is C ₁ -C ₄ alkyl.

In certain preferred embodiments of the present application, R ₁ in formula (VII) is C ₁ -C ₄ alkyl.

In certain preferred embodiments of the present application, R ₁ in formula (VI) is methyl, ethyl or propyl.

In certain preferred embodiments of the present application, R ₁ in formula (VII) is methyl, ethyl or propyl.

In certain preferred embodiments of the present application, R ₁ in formula (VI) is methyl or ethyl.

In certain preferred embodiments of the present application, R ₁ in formula (VII) is methyl or ethyl.

In certain preferred embodiments of the present application, R ₁ in formula (VI) is methyl.

In certain preferred embodiments of the present application, R ₁ in formula (VII) is methyl.

In certain preferred embodiments of the present application, R ₂ in formula (VI) or formula (VII) is C ₁ -C ₄ alkyl.

In certain preferred embodiments of the present application, R ₂ in formula (VI) is C ₁ -C ₄ alkyl.

In certain preferred embodiments of the present application, R ₂ in formula (VII) is C ₁ -C ₄ alkyl.

In certain preferred embodiments of the present application, R ₂ in formula (VI) is methyl, ethyl or propyl.

In certain preferred embodiments of the present application, R ₂ in formula (VII) is methyl, ethyl or propyl.

In certain preferred embodiments of the present application, R ₂ in formula (VI) is methyl or ethyl.

In certain preferred embodiments of the present application, R ₂ in formula (VII) is methyl or ethyl.

In certain preferred embodiments of the present application, R ₂ in formula (VI) is methyl.

In certain preferred embodiments of the present application, R ₂ in formula (VII) is methyl.

In certain preferred embodiments of the present application, the compound is selected from the group consisting of

Another aspect of the present application relates to a pharmaceutical composition comprising a compound, a prodrug, a stereoisomer or a pharmaceutically acceptable salt thereof, as described herein, and one or more pharmaceutical excipients.

The medicinal excipient refers to an excipient and an additive used in the production of a medicine and a prescription, and refers to a substance which has been evaluated for safety in addition to the active ingredient and which is included in the pharmaceutical preparation. . In addition to prototyping, acting as a carrier and improving stability, pharmaceutical excipients also have important functions such as solubilization, solubilization, and controlled release, which are important components that may affect the quality, safety and effectiveness of drugs. According to its source, it can be divided into natural materials, semi-synthetic materials and total synthetic materials. According to its action and use, it can be divided into: solvent, propellant, solubilizer, cosolvent, emulsifier, colorant, binder, disintegrant, filler, lubricant, wetting agent, osmotic pressure regulator, stabilizer, Glidants, flavoring agents, preservatives, suspending agents, coating materials, fragrances, anti-adhesives, antioxidants, chelating agents, penetration enhancers, pH adjusters, buffers, plasticizers, surface active agents Agent, foaming agent, antifoaming agent, thickener, inclusion agent, moisturizer, absorbent, diluent, flocculant and deflocculant, filter aid, release retardant, etc.; For oral, injection, mucosal, transdermal or topical administration, nasal or oral inhalation and ocular administration. The same pharmaceutical excipient can be used for pharmaceutical preparations of different administration routes, and has different effects and uses.

The pharmaceutical composition can be formulated into various suitable dosage forms depending on the route of administration. Wherein, the pharmaceutical composition or a suitable dosage form may contain 0.01 mg to 1000 mg of the compound of the present invention, a prodrug, a stereoisomer or a pharmaceutically acceptable salt thereof, suitably containing 0.1 mg to 800 mg, preferably 0.5- 500 mg, preferably from 1 to 350 mg, preferably from 5 to 250 mg, preferably from 5 to 150 mg, preferably from 5 to 100 mg.

When administered orally, the pharmaceutical composition can be formulated into any orally acceptable preparation including, but not limited to, tablets, capsules, granules, pills, syrups, oral solutions, oral suspensions, and oral emulsions. Wait. Among them, the carrier used for the tablet generally includes lactose and corn starch, and a lubricant such as magnesium stearate may also be added. The diluent used in the capsules generally includes lactose and dried corn starch. Oral suspensions are usually prepared by admixing the active ingredient with suitable emulsifying and suspending agents. Optionally, some sweeteners, fragrances or colorants may also be added to the above oral formulation forms.

When administered transdermally or topically, the pharmaceutical compositions may be in the form of a suitable ointment, lotion or lozenge, wherein the active ingredient is suspended or dissolved in one or more carriers. Carriers that can be used in ointment formulations include, but are not limited to, minerals Oil, liquid petrolatum, white petrolatum, propylene glycol, polyethylene oxide, polypropylene oxide, emulsifying wax and water; detergents or elixirs may be used, including but not limited to: mineral oil, sorbitan monostearate Tween 60, cetyl ester wax, hexadecene aromatic alcohol, 2-octyldodecanol, benzyl alcohol and water.

The pharmaceutical composition can also be administered in the form of an injection, including an injection, a sterile powder for injection, and a concentrated solution for injection. Among them, carriers and solvents which can be used include water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils may also be employed as a solvent or suspension medium such as a monoglyceride or a diglyceride.

Another aspect of the present application relates to a compound, prodrug, stereoisomer or pharmaceutically acceptable salt thereof, or use of the pharmaceutical composition, in the preparation of a reagent for inhibiting STAT3 expression.

Another aspect of the present application relates to a compound, prodrug, stereoisomer or pharmaceutically acceptable salt thereof, or use of the pharmaceutical composition, in the preparation of an agent that inhibits STAT3 activation.

Another aspect of the present application relates to a compound, prodrug, stereoisomer or pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for inhibiting STAT3 phosphorylation (e.g., inhibiting STAT3 705 tyrosine) Use of a reagent for phosphorylation or phosphorylation of STAT3 at position 727.

Another aspect of the present application relates to a compound, prodrug, stereoisomer or pharmaceutically acceptable salt thereof, or use of the pharmaceutical composition, in the manufacture of a STAT3 inhibitor.

Another aspect of the present application relates to a compound, prodrug, stereoisomer or pharmaceutically acceptable salt thereof, or use of the pharmaceutical composition, for the manufacture of a medicament for preventing or treating a disease associated with STAT3.

Another aspect of the present application relates to a compound, prodrug, stereoisomer or pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for use in the prevention or treatment of a disease associated with STAT3.

Another aspect of the present application relates to a method of preventing or treating a disease associated with STAT3 comprising administering to a subject in need thereof an effective amount of a compound described herein, a prodrug thereof, a stereoisomer or a pharmaceutical An acceptable salt or a step of the pharmaceutical composition.

In certain preferred embodiments of the present application, the disease associated with STAT3 is a tumor.

In certain preferred embodiments of the present application, the tumor is a solid tumor or a hematological tumor.

In certain preferred embodiments of the present application, the solid tumor is colorectal cancer, gastric cancer, breast cancer, pancreatic cancer, or lung cancer.

In certain preferred embodiments of the present application, the hematological tumor is lymphoma, myeloma, lymphocytic leukemia or acute myeloid leukemia.

Another aspect of the present application relates to the use of a compound, prodrug, stereoisomer or pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present application, in the manufacture of a medicament for inhibiting tumor cell proliferation.

In certain preferred embodiments of the present application, the tumor cell is selected from the group consisting of cancer cells of colon cancer, breast cancer, colon cancer, and lung cancer.

In certain preferred embodiments of the present application, the tumor cells are selected from the group consisting of SW620, MCF7, MDA-MD-231, LOVO, H1975, and Colon 205.

Another aspect of the present application relates to a compound, a prodrug, a stereoisomer or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described herein, in the manufacture of a medicament for the prevention and/or treatment of a tumor use.

In certain preferred embodiments of the present application, the tumor is selected from the group consisting of colon cancer, breast cancer, colorectal cancer, and lung cancer.

Another aspect of the present application relates to a method of inhibiting tumor cell proliferation in vivo or in vitro, comprising administering to a subject in need thereof an effective amount of a compound described herein, a prodrug thereof, a stereoisomer, or a pharmaceutically acceptable Salt or a pharmaceutical composition as described herein.

In certain preferred embodiments of the present application, the tumor cell is selected from the group consisting of cancer cells of colon cancer, breast cancer, colon cancer, and lung cancer.

In certain preferred embodiments of the present application, the tumor cells are selected from the group consisting of SW620, MCF7, MDA-MD-231, LOVO, H1975, and Colon 205.

Another aspect of the present application relates to a method of preventing and/or treating a tumor comprising administering to a subject in need thereof an effective amount of a compound, prodrug, stereoisomer or pharmaceutically acceptable salt thereof, or The medicine described in the present application Composition.

In certain preferred embodiments of the present application, the tumor is selected from the group consisting of colon cancer, breast cancer, colorectal cancer, and lung cancer.

Another aspect of the invention relates to a compound, prodrug, stereoisomer or pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein for use in inhibiting STAT3.

Another aspect of the invention relates to a compound, prodrug, stereoisomer or pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described herein for use in inhibiting tumor cell proliferation or for preventing and/or Treat tumors.

In certain preferred embodiments of the present application, the tumor cell is selected from the group consisting of cancer cells of colon cancer, breast cancer, colon cancer, and lung cancer.

In certain preferred embodiments of the present application, the tumor is selected from the group consisting of colon cancer, breast cancer, colorectal cancer, and lung cancer.

In certain preferred embodiments of the present application, the tumor cells are selected from the group consisting of SW620, MCF7, MDA-MD-231, LOVO, H1975, and Colon 205.

In the present invention, the scientific and technical terms used herein have the meanings commonly understood by those skilled in the art, unless otherwise stated. Moreover, the cell culture and immunological laboratory procedures used herein are routine steps that are widely used in the corresponding art. Also, for a better understanding of the present invention, definitions and explanations of related terms are provided below.

As used herein, the term "stereoisomer" includes conformational isomers and configurational isomers, wherein the configurational isomers primarily include cis and trans isomers and optical isomers. The compounds of the invention may exist in stereoisomeric forms and thus encompass all possible stereoisomeric forms, as well as any combination or any mixture thereof. For example, a single enantiomer, a single diastereomer or a mixture of the above. When the compound of the present invention contains an olefinic double bond, it includes a cis isomer and a trans isomer, and any combination thereof, unless otherwise specified.

As used herein, the term "pharmaceutically acceptable salts" refers to (1) a compound of the present invention, in the presence of acidic functional group (e.g. -COOH, -OH, -SO ₃ H, etc.) with a suitable inorganic or organic a salt formed by a cation (base), for example, a salt of a compound of the invention with an alkali metal or alkaline earth metal, an ammonium salt of a compound of the invention, and a salt of a compound of the invention with a nitrogen-containing organic base; and (2) a compound of the invention A salt of a basic functional group (e.g., -NH ₂ or the like) which is formed with a suitable inorganic or organic anion (acid), such as a salt of a compound of the present invention with an inorganic acid or an organic carboxylic acid.

Thus, "pharmaceutically acceptable salts" of the compounds of the invention include, but are not limited to, alkali metal salts such as sodium, potassium, lithium, and the like; alkaline earth metal salts such as calcium, magnesium, and the like; other metal salts, Such as aluminum salt, iron salt, zinc salt, copper salt, nickel salt, cobalt salt, etc.; inorganic alkali salt, such as ammonium salt; organic alkali salt, such as t-octylamine salt, dibenzylamine salt, morpholine salt, Portuguese Glycosylamine salt, phenylglycine alkyl ester salt, ethylenediamine salt, N-methylglucamine salt, sulfonium salt, diethylamine salt, triethylamine salt, dicyclohexylamine salt, N, N'- Dibenzylethylenediamine salt, chloroprocaine salt, procaine salt, diethanolamine salt, N-benzyl-phenethylamine salt, piperazine salt, tetramethylamine salt, tris (hydroxyl) Aminomethane salt; hydrohalide salt such as hydrofluoric acid salt, hydrochloride salt, hydrobromide salt, hydroiodide salt, etc.; inorganic acid salt such as nitrate, perchlorate, sulfate, phosphate And lower; alkanesulfonates such as methanesulfonate, triflate, ethanesulfonate, etc.; arylsulfonates such as besylate, p-benzenesulfonate, etc.; Such as acetate, malate, Fuma Salt, succinate, citrate, tartrate, oxalate, maleate, etc.; amino acid salts such as glycinate, trimethylglycine, arginine, ornithine, glutamate , aspartate and the like.

As used herein, the term "prodrug", also referred to as prodrug, prodrug, prodrug, etc., means that the compound of the present application is modified to be inactive or less active in vitro, in vivo. An enzyme or non-enzymatic conversion that releases the active drug to exert a pharmacological effect. The design principles and preparation methods of prodrugs are known to those skilled in the art.

As used herein, the term "halogen" refers to fluoro, chloro, bromo and iodo.

As used herein, the term "C ₁ -C ₆ alkyl" refers to a straight or branched alkyl group having from 1 to 6 carbon atoms, for example, C ₁ -C ₄ alkyl, C ₁ -C ₂ alkane. A group, a C ₁ alkyl group, a C ₂ alkyl group, a C ₃ alkyl group, a C ₄ alkyl group, a C ₅ alkyl group or a C ₆ alkyl group. Specific examples include, but are not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl, and the like.

As used herein, the term "C ₁ -C ₆ alkoxy" refers to a group formed in the C ₁ -C ₆ alkyl-O- form, wherein "C ₁ -C ₆ alkyl" is as defined As mentioned above. Specific examples include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, butoxy, 2-butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentane Oxyl, hexyloxy, and the like.

As used herein, the term "C ₁ -C ₆ alkylamino" refers to a group formed in the C ₁ -C ₆ alkyl-NH- form, wherein "C ₁ -C ₆ alkyl" is as defined above Said. Specific examples include, but are not limited to, methylamino, ethylamino, propylamino, isopropylamino, butylamino, 2-butylamino, isobutylamino, sec-butylamino, tert-butylamino, pentylamino, hexylamino, and the like.

As used herein, the term "C ₁ -C ₆ alkylthio" refers to a group formed in the C ₁ -C ₆ alkyl-S- mode, wherein "C ₁ -C ₆ alkyl" is as defined As mentioned above. Specific examples include, but are not limited to, methylthio, ethylthio, propylthio, isopropylthio, butylthio, 2-butylthio, isobutylthio, sec-butylthio, tert-butylthio, pentane Sulfur-based, hexylthio, and the like.

As used herein, the term "C ₁ -C ₆ alkylsulfonyl" refers to a group formed in the manner of C ₁ -C ₆ alkyl-S(O) ₂ -, wherein "C ₁ -C ₆ alkane The definition of "base" is as described above. Specific examples include, but are not limited to, methylsulfonyl, ethylsulfonyl, and the like.

As used herein, the term "C ₂ -C ₆ alkenyl" refers to a straight or branched chain hydrocarbon radical containing from 2 to 6 carbon atoms and one, two or three carbon-carbon double bonds, preferably containing one carbon Carbon double bond C ₂ -C ₆ alkenyl. For example, C ₂ -C ₄ alkenyl, C ₂ alkenyl, C ₃ alkenyl, C ₄ alkenyl, C ₅ alkenyl or C ₆ alkenyl. Specific examples include, but are not limited to, ethenyl, propenyl, 2-propenyl, butenyl, 2-butenyl, 2-methyl-propenyl, butadienyl, pentenyl, 2-methyl- Butenyl, 3-methyl-butenyl, 1,3-pentadienyl, 1,4-pentadienyl, hexenyl, 2-ethyl-butenyl, 3-methyl-pentyl Alkenyl, 4-methyl-pentenyl, 1,3-hexadienyl, 1,4-hexadienyl, 1,5-hexadienyl and the like.

As used herein, the term "C ₂ -C ₆ alkynyl" refers to a straight or branched chain hydrocarbon radical containing from 2 to 6 carbon atoms and one, two or three carbon-carbon triple bonds, preferably containing one carbon a C ₃ -C ₆ alkynyl group having a carbon triple bond. For example, C ₂ -C ₄ alkynyl, C ₂ alkynyl, C ₃ alkynyl, C ₄ alkynyl, C ₅ alkynyl or C ₆ alkynyl. Specific examples include, but are not limited to, ethynyl, propynyl, 2-propynyl, butynyl, 2-butynyl, 2-methyl-propynyl, butadiynyl, pentynyl, 2- Methyl-butynyl, 3-methyl-butynyl, 1,3-pentadiynyl, 1,4-pentadiynyl, hexynyl, 2-ethyl-butynyl, 3-methyl A pentynynyl group, a 4-methyl-pentynyl group, a 1,3-hexadiynyl group, a 1,4-hexadiynyl group, a 1,5-hexadiynyl group, and the like.

As used herein, the term "aryl" refers to a monocyclic or polycyclic hydrocarbon group having an aromatic character, such as a 6-10 membered aryl group and the like. Specific examples include, but are not limited to, phenyl, naphthyl, anthracenyl, phenanthryl, and the like.

As used herein, the term "heteroaryl" refers to containing at least one heteroatom selected from N, as described above heteroatoms O and S aryl group, for example C ₅ -C ₆ heteroaryl. Specific examples include, but are not limited to, furyl, thienyl, pyrrolyl, thiazolyl, isothiazolyl, thiadiazolyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, 1,2,3- Triazolyl, 1,2,4-triazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3 , 4-oxadiazolyl, pyridyl, 2-pyridinone, 4-pyridinone, pyrimidinyl, 2H-1,2-oxazinyl, 4H-1,2-oxazinyl, 6H-1, 2-oxazinyl, 4H-1,3-oxazinyl, 6H-1,3-oxazinyl, 4H-1,4-oxazinyl, pyridazinyl, pyrazinyl, 1,2,3- Triazinyl, 1,3,5-triazinyl, 1,2,4,5-tetraazinyl, azepanene, 1,3-diazepine, benzofuran , benzoisofuranyl, benzothienyl, fluorenyl, isoindole, benzoxazolyl, benzimidazolyl, oxazolyl, benzotriazolyl, quinolinyl, 2-quinoline Ketone, 4-quinolinone, 1-isoquinolinone, isoquinolyl, acridinyl, phenanthryl, benzoxazinyl, pyridazinyl, quinazolinyl, quinoxalinyl, phenolphthalein Base, acridinyl, fluorenyl, naphthyridinyl, phenazine, phenothiazine, and the like.

As used herein, the term "C ₃ -C ₆ cycloalkyl" refers to a monocyclic saturated alkyl group containing 3 to 6 ring members, such as a 3-5 membered cycloalkyl group, 3 members, 4 members, 5 Yuan, 6-membered cycloalkyl. Specific examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.

As used herein, the term "C ₃ -C ₆ cycloalkylmethyl" refers to a group formed as a C ₃ -C ₆ cycloalkyl-CH ₂ - group, wherein C ₃ -C ₆ cycloalkyl The definition is as described above. Specific examples include, but are not limited to, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, and the like.

The beneficial effects of the invention are at least one of the following:

1. The inventors have discovered a class of compounds of formula (I) which, in a variety of tumor cells, also significantly inhibits the expression level of STAT3; said compounds significantly inhibit the phosphorylation of STAT3, such as STAT3705 Phosphorylation of tyrosine, such as phosphorylation of serine at position 7273, inhibits STAT3 activation. Thus, the compounds of the present application act as STAT3 inhibitors for the treatment of diseases associated with STAT3, such as tumors.

2. The compound of the present invention, a prodrug thereof, a stereoisomer or a pharmaceutically acceptable salt thereof is active for inhibiting proliferation of tumor cells, particularly for inhibiting proliferation of cancer cells of colon cancer, breast cancer, colon cancer and lung cancer.

3. The compounds of the invention, prodrugs, stereoisomers or pharmaceutically acceptable salts thereof have good pharmacokinetic properties.

DRAWINGS

Figure 1 shows the results of immunoblot analysis of STAT3 and phosphorylated STAT3 in SW480 cells treated with different concentrations of Compound 1 and BBI608, respectively, under different time conditions.

Figure 2 shows the results of immunoblot analysis of STAT3 and phosphorylated STAT3 in K562 cells treated with different concentrations of Compound 1 and BBI608, respectively, under different time conditions.

Figure 3 shows the results of immunoblot analysis of total STAT3 and p-Stat3 (Tyr705) in SW480 cells and K562 cells treated with different concentrations of Compound 2, Compound 3 and BBI608, respectively, under different time conditions.

Figure 4 shows the treatment with different concentrations of Compound 2, Compound 3 and BBI608, respectively, at different times The results of immunoblot analysis of total STAT3 and p-Stat3 (Ser727) in SW480 cells and K562 cells were detected.

Figure 5 shows the pharmacokinetic results of Compound 2 administered orally in rats.

Figure 6 shows the pharmacokinetic results of Compound 3 administered orally in rats.

detailed description

The embodiments of the present invention will be described in detail below with reference to the accompanying drawings, however, the following examples are intended to illustrate the invention and are not intended to limit the scope of the invention. Those who do not specify the specific conditions in the examples are carried out according to the conventional conditions or the conditions recommended by the manufacturer. The reagents or instruments used are not indicated by the manufacturer, and are conventional products that can be obtained commercially.

The compounds of the invention can be prepared by the following synthetic routes:

Route 1:

Route 2:

Route 3:

Example 1 2-Acetylfuro[3,2-g]quinoline-4,9-dione Preparation of (2-acetylfuro[3,2-g]quinoline-4,9-dione, compound 1)

The title compound can be prepared by the aforementioned route 1:

Step 1a: 1-(4,6-Dibromo-7-hydroxybenzofuran-2-yl)ethyl-1-one (1-(4,6-dibromo-7-hydroxybenzofuran-2-yl)ethan- 1-one, Preparation of Compound 102-1): 2-Acetyl-7-hydroxybenzofuran (1.76 g, 10 mmol, 1.0 eq.) was dissolved in dichloromethane (100 mL). Aluminum (5.32 g, 40 mmol, 4.0 eq.), the mixture was stirred for 40 hrs in an oil bath for 1 hour, and then bromine (3.52 g, 22 mmol, 2.2 eq. The solution was kept for one hour and the reaction was continued for 16 hours. Ice water (100 ml) was added to the reaction flask, and washed with water to give 1-(4,6-dibromo-7-hydroxybenzofuran-2-yl)ethyl-1-one (3 g, yield 89.8%) ). LCMS (ESI): m / z 335.0 [M + 1] +.

Step 1b: Preparation of 2-acetyl-6-bromobenzofuran-4,7-dione (2-acetyl-6-bromobenzofuran-4,7-dione, compound 103-1): 1-(4, 6-Dibromo-7-hydroxybenzofuran-2-yl)ethyl-1-one (Compound 102-1) (0.334 g, 1 mmol, 1.0 eq.) was dissolved in acetic acid (7.5 mL). Chromium trioxide (0.22 g, 2.2 mmol, 2.2 eq.) was stirred at room temperature for 1 hour. Add water (100 ml) to the reaction mixture, and then add dichloromethane (100 ml) to extract, then separate the methylene chloride layer, and then concentrated to give 2-acetyl-6-bromobenzofuran-4,7- Dione (0.21 g, yield 78%). LCMS (ESI): m / z 269.0 [M + 1] +.

Step 1c: Preparation of (E)-N'-allyl-N,N-dimethylindole ((E)-N'-allylidene-N, N-dimethylhydrazine, compound 105-1): acrolein (Compound 104-1) (0.56 g, 10 mmol, 1.0 eq.) was dissolved in dichloromethane (10 mL), then dimethyl hydrazine (0.6 g, 10 mmol, 1.0 eq.) and acetic acid (1 ml) The reaction was stirred for 1 hour under ice water bath. After 10 ml of water was added to the reaction mixture, the methylene chloride layer was separated and concentrated to give (E)-N'-allyl-N,N-dimethylindole (0.8 g, yield: 81.4%). LCMS (ESI): m / z99.2 [M + 1] +.

Step 1d: Preparation of 2-acetylfuro[3,2-g]quinoline-4,9-dione (2-acetylfuro[3,2-g]quinoline-4,9-dione, compound 1): 2-Acetyl-6-bromobenzofuran-4,7-dione (Compound 103-1) (100 mg, 0.37 mmol, 1.0 eq.) was dissolved in dichloromethane (10 mL). E)-N'-Allyl-N,N-dimethylindole (Compound 105-1) (36 mg, 0.37 mmol, 1.0 eq.). Water (20 ml) was added to the reaction mixture, and the mixture was stirred, and the methylene chloride layer was separated, dried and concentrated. The concentrated residue was chromatographed with dichloromethane and methanol to give 2-acetylfuran. [3,2-g] Quinoline-4,9-dione (66 mg, yield 74.1%). Mp 180-185 ℃; LCMS (ESI): m / z 242.1 [M + 1] +1; 1 HNMR: (600MHz, CDCl 3) δ2.69 (s, 3H), 7.64 (s, 1H), 7.75 ( Dd, J = 4.6 Hz, 7.8 Hz, 1H), 8.57 (dd, J = 7.8 Hz, 1.6 Hz, 1H), 8.10 (dd, J = 4.6 Hz, 1.6 Hz, 1H).

Example 2 2-Acetyl-6-methylfuro[3,2-g]quinoline-4,9-dione Preparation of (2-acetyl-6-methylfuro[3,2-g]quinoline-4,9-dione, compound 2)

Step 2a: (E)-N,N-Dimethyl-N'-(2-methylallyl-propyl)hydrazine ((E)-1,1-dimethyl-2-(2-methylallylidene)hydrazine, Compound 105 -2) Preparation: 2-Methylpropenal (Compound 104-2) (0.70 g, 10 mmol, 1.0 eq.) was dissolved in dichloromethane (10 mL). The reaction was stirred for 1 hour under ice-water bath with 10 mmol, 1.0 eq. After adding 10 ml of water to the reaction mixture, the methylene chloride layer was separated and dried to give (E)-N,N-dimethyl-N'-(2-methylallyl-propylidene) (0.7 g, yield 62.5 %).

Step 2b: 2-Acetyl-6-methylfuro[3,2-g]quinoline-4,9-dione (2-acetyl-6-methylfuro[3,2-g]quinoline-4,9 -dione, preparation of compound 2): 2-acetyl-6-bromobenzofuran-4,7-dione (compound 103-1) (40 mg, 0.15 mmol, 1.0 eq.) was dissolved in dichloromethane (10 ml) was further charged with (E)-N,N-dimethyl-N'-(2-methylallylpropene) oxime (Compound 105-2) (18.5 mg, 0.16 mmol, 1.0 eq.) The reaction was stirred at room temperature for 30 minutes. Water (20 ml) was added to the reaction mixture, and the mixture was evaporated to dryness. The methylene chloride layer was dried and concentrated. The concentrated residue was chromatographed with dichloromethane and methanol to give 2-acetyl-6-methyl. Furo[3,2-g]quinoline-4,9-dione (29 mg, yield 76.3%). Mp 220-224 ℃; LCMS (ESI): m / z 256.3 [M + 1] +; 1 HNMR: (600MHz, CDCl 3) δ2.69 (s, 3H), 7.64 (s, 1H), 7.75 (dd , J = 4.6 Hz, 7.8 Hz, 1H), 8.57 (dd, J = 7.8 Hz, 1.6 Hz, 1H), 8.10 (dd, J = 4.6 Hz, 1.6 Hz, 1H).

Example 3 2-Acetyl-6-ethylfuro[3,2-g]quinoline-4,9-dione Preparation of (2-acetyl-6-ethylfuro[3,2-g]quinoline-4,9-dione, compound 3)

Step 3a: (E)-N,N-Dimethyl-N'-(2-methylenebutylene) hydrazine ((E)-1, 1-dimethyl-2-(2-methylenebutylidene) hydrazine, compound 105 Preparation of -3): 2-Ethyl acrolein (Compound 104-3) (0.186 g, 2 mmol, 1.0 eq.) was dissolved in dichloromethane (10 mL) and then dimethyl hydrazine (0.12 g) The reaction was stirred for 1 hour under ice-water bath with 2 mmol, 1.0 eq. After adding 10 ml of water to the reaction mixture, the mixture was washed with methylene chloride, and then dried to give (E)-N,N-dimethyl-N'-(2-methylenebutylene) oxime (0.2 g, yield 79.3) %).

Step 3b: 2-Acetyl-6-ethylfuro[3,2-g]quinoline-4,9-dione (2-acetyl-6-ethylfuro[3,2-g]quinoline-4,9 -dione, preparation of compound 3): 2-acetyl-6-bromobenzofuran-4,7-dione (compound 103-1) (114 mg, 0.42 mmol, 1.0 eq.) was dissolved in dichloromethane (10 ml) was further charged with (E)-N,N-dimethyl-N'-(2-methylenebutylene) hydrazine (Compound 105-3) (54 mg, 0.42 mmol, 1.0 eq.) The reaction was stirred at room temperature for 30 minutes. Water (20 ml) was added to the reaction mixture, and the mixture was evaporated to dryness. The methylene chloride layer was evaporated to dryness, and then concentrated, and the residue was chromatographed with methylene chloride and methanol to give 2-acetyl-6-ethyl Furo[3,2-g]quinoline-4,9-dione (50 mg, yield 44.2%). Mp 200-203 ℃; LCMS (ESI): m / z 270.1 [M + 1] +; 1 HNMR: (600MHz, CDCl 3) δ1.37 (t, J = 1.6Hz, 3H), 2.68 (s, 1H ), 2.88 (dd, J = 15.2 Hz, 1.6 Hz, 2H), 7.62 (s, 1H), 8.36 (d, J = 2.2 Hz, 1H), 8.91 (d, J = 2.2 Hz, 1H).

Example 4 2-Acetyl-5-methylfuro[3,2-g]quinoline-4,9-dione Preparation of (2-acetyl-5-methylfuro[3,2-g]quinoline-4,9-dione, compound 5)

Step 4a: (E)-N'-((E)-2-butenylene)-N,N-dimethylhydrazine ((E)-N'-((E)-but-2-en-1 Preparation of -Nlidene)-N,N-dimethylhydrazine, compound 202-5): 2-butenal (compound 201-5) (0.14 g, 2 mmol, 1.0 eq.) was dissolved in dichloromethane (10 ml) The reaction was further stirred for 1 hour while further adding dimethylhydrazine (0.12 g, 2 mmol, 1.0 eq.) and acetic acid (0.5 ml) in ice water. After adding 10 ml of water to the reaction mixture, the methylene chloride layer was separated and dried to give (E)-N'-((E)-2-butenyl)-N,N-dimethylindole (0.158 g, The rate is 69.9%).

Step 4b: 2-Acetyl-5-methylfuro[3,2-g]quinoline-4,9-dione (2-acetyl-5-methylfuro[3,2-g]quinoline-4,9 -dione, preparation of compound 5): 2-acetyl-6-bromobenzofuran-4,7-dione (103-1) (80 mg, 0.295 mmol, 1.0 eq.) was dissolved in toluene (10 ml) In addition, (E)-N'-((E)-2-butenylene)-N,N-dimethylhydrazine (Compound 202-5) (33 mg, 0.295 mmol, 1.0 eq.) oil The reaction was stirred at 100 ° C for 2 hours. Water (20 ml) was added to the reaction mixture, and the mixture was evaporated to dryness, and then evaporated toluene, and then concentrated, and the residue was purified by ethyl acetate and n-hexanes to give 2-acetyl-5-methylfuran. [3,2-g] Quinoline-4,9-dione (25 mg, yield 33.3%). Melting point 233-236 ° C; LCMS (ESI): m/z 256.0 [M+1] ⁺ ; ¹ H NMR: (600 MHz, CDCl ₃ ) δ 2.67 (s, 3H), 2.88 (s, 3H), 7.49 (d) , J = 4.8 Hz, 1H), 7.59 (s, 1H), 8.87 (d, J = 4.8 Hz, 1H).

Example 5 2-Acetyl-5-ethylfuro[3,2-g]quinoline-4,9-dione Preparation of (2-acetyl-5-ethylfuro[3,2-g]quinoline-4,9-dione, compound 6)

Step 5a: (E)-N,N-Dimethyl-N'-((E)-2-pentopentyl)anthracene ((E)-N,N-dimethyl-N'-((E)- Preparation of pent-2-en-1-ylidene)hydrazine, compound 202-6): 2-pentenal (compound 201-6) (0.168 g, 2 mmol, 1.0 eq.) was dissolved in dichloromethane (10) In ML), dimethyl hydrazine (0.12 g, 2 mmol, 1.0 eq.) and acetic acid (0.5 ml) were further added and the mixture was stirred for 1 hour. After adding 10 ml of water to the reaction mixture, the methylene chloride layer was separated and dried to give (E)-N,N-dimethyl-N'-((E)-2-pentenylene) oxime (0.139 g, Yield 55.1%).

Step 5b: 2-Acetyl-5-ethylfuro[3,2-g]quinoline-4,9-dione (2-acetyl-5-ethylfuro[3,2-g]quinoline-4,9 Preparation of -dione, compound 6): 2-acetyl-6-bromobenzofuran-4,7-dione (compound 103-1) (100 mg, 0.37 mmol, 1.0 eq.) was dissolved in toluene (10) (ml) plus (E)-N,N-dimethyl-N'-((E)-2-pentopentyl)indole (Compound 202-6) (46.6 mg, 0.37 mmol, 1.0 eq. The reaction was stirred for 2 hours in an oil bath at 100 °C. Water (20 ml) was added to the reaction mixture, and the mixture was evaporated to dryness, and then evaporated toluene, and then concentrated, and the residue was purified by ethyl acetate and n-hexanes to give 2-acetyl-5-ethylfuran. [3,2-g] Quinoline-4,9-dione (22 mg, yield 22.1%). Mp 210-213 ℃; LCMS (ESI): m / z 270.1 [M + 1] +; 1 HNMR: (600MHz, CDCl 3) δ1.33 (t, J = 7.4Hz, 3H), 2.76 (s, 3H ), 3.33 (dd, J = 14.9 Hz, J = 7.4 Hz, 2H), 7.53 (d, J = 4.9 Hz, 1H), 7.60 (s, 1H), 8.91 (d, J = 4.9 Hz, 1H).

Example 6 2-Acetyl-5-furan-2-yl-furo[3,2-g]quinoline-4,9-dione Preparation of (2-acetyl-5-(furan-2-yl)furo[3,2-g]quinoline-4,9-dione, compound 13)

Step 6a: (E)-N'-((E)-3-furan-2-yl-p-propylidene)-N,N-dimethylindole ((E)-2-((E)-3- Preparation of (furan-2-yl)allylidene)-1,1-dimethylhydrazine, compound 202-13): 3-(2-furyl)propenal (compound 201-13) (0.224 g, 2 mmol, 1.0) Equivalent) was dissolved in dichloromethane (10 mL), and dimethyl hydrazine (0.12 g, 2 mmol, 1.0 eq.) and acetic acid (0.5 mL) After adding 10 ml of water to the reaction mixture, the methylene chloride layer was separated and dried to give (E)-N'-((E)-3-furan-2-yl-p-propylidene)-N,N-dimethyl肼 (0.2 g, yield 60.9%). LCMS (ESI): m / z 165.2 [M + 1] +.

Step 6b: 2-Acetyl-5-furan-2-yl-furo[3,2-g]quinoline-4,9-dione (2-acetyl-5-(furan-2-yl)furo [ Preparation of 3,2-g]quinoline-4,9-dione, compound 13): 2-acetyl-6-bromobenzofuran-4,7-dione (compound 103-1) (43 mg, 0.158) Millimol, 1.0 eq.) was dissolved in toluene (10 mL), followed by (E)-N'-((E)-3-furan-2-yl-isopropylidene)-N,N-dimethylhydrazine (Compound 202-13) (26 mg, 0.158 mmol, 1.0 eq.). Water (20 ml) was added to the reaction mixture, and the mixture was evaporated to dryness, and then evaporated toluene, and then evaporated. The residue was concentrated to ethyl acetate and n-hexanes to give 2-acetyl-5-furan-2- Base-furo[3,2-g]quinoline-4,9-dione (15 mg, yield 30.9%). LCMS (ESI): m / z 308.0 [M + 1] +; 1 HNMR: (600MHz, CDCl 3) δ2.68 (s, 3H), 6.64 (dd, J = 3.4Hz, 1.7Hz, 1H), 7.26 (d, J = 2.7 Hz, 1H), 7.59 (s, 1H), 7.65 (d, J = 1.0 Hz, 1H), 7.90 (d, J = 5.1 Hz, 1H), 9.00 (d, J = 5.0 Hz) , 1H).

Example 7 2-Acetylfuro[2,3-g]quinoline-4,9-dione Preparation of (2-acetylfuro[2,3-g]quinoline-4,9-dione, compound 20)

Step 7a: Preparation of 2-(3-butyn-2-yloxy)tetrahydro-2H-pyran (2-(but-3-yn-2-yloxy)tetrahydro-2H-pyran, compound 302): Compound p-toluenesulfonic acid (0.1 g, 0.58 mmol), 3-butyn-2-ol (5.0 g, 71.4 mmol) and 3,4-dihydro-2H-pyran (6.0 g, 71.4 mmol) Dissolved in 50 ml of dichloromethane and stirred at room temperature overnight. The reaction solution was quenched with water and then ethyl acetate. The obtained organic phase is washed with saturated brine, dried over anhydrous sodium sulfate and evaporated. Alkyn-2-oxy)tetrahydro-2H-pyran (4.8 g, yield: 41%). ¹ H NMR (400 MHz, CDCl ₃ ): δ 1.47 (s, 3H), 1.53-1.63 (m, 4H), 1.71-1.87 (m, 2H), 2.38 (s, 2H), 3.52-3.55 (m, 1H) ), 3.79-3.85 (m, 1H), 4.52-4.58 (m, 1H), 4.94 (m, 1H).

Step 7b: 2-(1-(tetrahydro-2H-pyran-2-oxy)ethyl)-4-hydroxybenzofuran (2-(1-(Tetrahydro-2H-pyran-2-yloxy)ethyl) Preparation of benzofuran-4-ol, compound 304): Under the protection of nitrogen, the compound 2-(3-butyn-2-yloxy)tetrahydro-2H-pyran (compound 302) (1.7 g, 11.0 mmol) , 1,3-dihydroxy-2-iodobenzene (compound 303) (1.3 g, 5.5 mmol), di-triphenylphosphine palladium dichloride (135 mg, 0.2 mmol), cuprous iodide ( 56 mg, 0.3 mmol) and triethylamine (5 ml) were dissolved in 5 ml of N,N-dimethylformamide and stirred at 60 °C overnight. The reaction solution was cooled to room temperature, quenched with water and then ethyl acetate. The obtained organic phase is washed with saturated brine, dried over anhydrous sodium sulfate and evaporated. Tetrahydro-2H-pyran-2-oxy)ethyl)-4-hydroxybenzofuran (900 mg, yield: 63%). ¹ H NMR (400 MHz, CDCl ₃ ): δ 1.57-1.65 (m, 7H), 1.75-1.86 (m, 2H), 3.57-3.61 (m, 1H), 3.85-3.91 (m, 1H), 4.88 (q) , J = 6.8 Hz, 1H), 5.06-5.08 (m, 1H), 5.85 (s, 2H), 6.50 (d, J = 8.0 Hz, 2H), 7.12 (t, J = 8.0 Hz, 1H).

Step 7c: 2-(1-(tetrahydro-2H-pyran-2-oxy)ethyl)benzofuran-4,7-dione (2-(1-(tetrahydro-2H-pyran-2-) Preparation of yloxy)ethyl)benzofuran-4,7-dione, compound 305): the compound 2-(1-(tetrahydro-2H-pyran-2-oxy)ethyl)-4-hydroxybenzofuran Compound 304) (800 mg, 3.0 mmol) in ethanol (5 ml) was added dropwise at 0 ° C to KH ₂ PO ₄ (0.6M, 15 mL) and potassium nitrite (2.0 g, 7.62 mmol) Among the 10 ml aqueous solutions. The reaction solution was stirred at 0 ° C for 1 hour and then at room temperature for 2 hours, then extracted with ethyl acetate. The obtained organic phase is washed with saturated brine, dried over anhydrous sodium sulfate and evaporated. Tetrahydro-2H-pyran-2-oxy)ethyl)benzofuran-4,7-dione (260 mg, yield: 31%).

Step 7d: Preparation of (E)-N'-allylacetyl hydrazide ((E)-N'-allylideneacetohydrazide, compound 308): Compound acrolein (Compound 306) (1.0 g, 17.8 mmol) and acetyl The hydrazine (Compound 307) (1.3 g, 17.8 mmol) was dissolved in ethanol (50 mL) The reaction solution was cooled to room temperature, quenched with water and then ethyl acetate. The obtained organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. The object compound (E)-N'-allylacetyl hydrazide (1.8 g, yield: 90%). ¹ H NMR (400 MHz, CDCl ₃ ): δ 2.28 (s, 3H), 5.58-5.64 (m, 2H), 6.42-6.51 (m, 1H), 7.46 (d, J = 9.2 Hz, 1H), 9.56 ( s, 1H).

Step 7e: Mixture 2-(1-(tetrahydro-2H-pyran-2-oxy)ethyl)furo[3,2-g]quinoline-4,9-dione (2-(1- ((tetrahydro-2H-pyran-2-yl)oxy)ethyl)furo[3,2-g]quinoline-4,9-dione, compound 309) and 2-(1-(tetrahydro-2H-pyran)- 2-oxy)ethyl)furo[2,3-g]quinoline-4,9-dione (2-(1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)furo[ Preparation of 2,3-g]quinoline-4,9-dione, compound 309'): Compound 2 (1-(tetrahydro-2H-pyran-2-yloxy)ethyl)benzofuran-4, 7-Diketone (Compound 305) (260 mg, 0.94 mmol) and compound (E)-N'-allylacetyl hydrazide (Compound 308) (263 mg, 2.36 mmol) dissolved in 25 mL of xylene The solution was stirred at 160 ° C for 48 hours. The reaction solution was cooled to room temperature, quenched with water and then ethyl acetate. The obtained organic phase was washed with brine, dried over anhydrous sodium sulfate An oil is obtained as a mixture of 2-(1-(tetrahydro-2H-pyran-2-oxy)ethyl)furo[3,2-g]quinoline-4,9-dione and 2-( 1-(tetrahydro-2H-pyran-2-oxy)ethyl)furo[2,3-g]quinoline-4,9-dione (45 mg, yield: 14%, two different Structure).

Step 7f: Mixture 2-(1-hydroxyethyl)furo[3,2-g]quinoline-4,9-dione (2-(1-hydroxyethyl)furo[3,2-g]quinoline-4 , 9-dione, compound 310) and 2-(1-hydroxyethyl)furo[2,3-g]quinoline-4,9-dione (2-(1-hydroxyethyl)furo[2,3- g] quinoline-4,9-dione, compound 310') Preparation: compound mixture 2-(1-(tetrahydro-2H-pyran-2-yloxy)ethyl)furan[3,2-g Quinoline-4,9-dione (compound 309) and 2-(1-(tetrahydro-2H-pyran-2-oxy)ethyl)furo[2,3-g]quinoline-4 , 9-diketone (compound 309') (260 mg, 0.94 mmol) was dissolved in 10 ml of 2N hydrogen chloride / tetrahydrofuran solution. After stirring at room temperature for 1 hour, the pH of the solution was adjusted with saturated sodium bicarbonate solution. To 8-9. It was then extracted with ethyl acetate. The obtained organic phase was washed with brine, dried over anhydrous sodium sulfate

Step 7g: Preparation of 2-acetylfuro[2,3-g]quinoline-4,9-dione (2-acetylfuro[2,3-g]quinoline-4,9-dione, compound 20): The mixture obtained in the previous step was crude 2-(1-hydroxyethyl)furo[3,2-g]quinolin-4,9-dione (compound 310) and 2-(1-hydroxyethyl)furan. [2,3-g]quinoline-4,9-dione (compound 310'), manganese dioxide (5.0 eq.) was suspended in 10 ml of dichloromethane, stirred at room temperature for 3 hours, filtered over Celite. After the filtrate was concentrated under reduced pressure, the obtained crude product was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate = 3/1) to give the first fraction compound (Rf=0.6) which was identified and compared with the standard compound 1 ( 2-acetylfuro[3,2-g]quinoline-4,9-dione) (12 mg). The obtained second fraction compound (Rf = 0.58) was Compound 20 (2-acetylfuro[2,3-g]quinolin-4,9-dione) (7 mg). ¹ H NMR (400 MHz, CDCl ₃ ): δ 2.68 (s, 3H), 7.70 (s, 1H), 7.75-7.78 (m, 1H), 8.61 (d, J = 8.0 Hz 1H), 9.10 (d, J) =7.2Hz 1H).

According to the preparation methods of Examples 1-7, the present application can also synthesize the following compounds:

Example 8 Biological Activity Test

I. Tumor cell proliferation inhibition experiment

Experimental method

Luminescent Cell Viability Assay kit(见厂家说明书)测定ATP的含量来评估细胞生长抑制。简要来讲，每个孔中加入30μl

试剂，摇板10分钟，诱导细胞裂解，用荧光/化学发光分析仪Fluoroskan Ascent FL(Thermo Scientific Fluoroskan Ascent FL)检测记录荧光信号。从二甲基亚砜(DMSO)处理72小时的细胞得到最大的信号值。从单独的培养基(细胞数为零)得到最小信号值定义为0。抑制率％＝(最大信号值-化合物信号值)/(最大信号值-最小信号值)X 100％。使用GraphPad Prism V5.0(GraphPad Software,San Diego,CA)软件处理数据。通过S形剂量-反应曲线拟合计算IC50值。Cell viability was assessed by measuring the amount of adenosine triphosphate (ATP) using the CellTiter-Glo Luminescent Cell Viability Assay Kit (Promega, #G7572, Madison, WI). Tumor cell lines were purchased from the Shanghai Fudan IBS Cell Resource Center and the American Type Culture Collection (ATCC). Cells were digested with trypsin from cell culture dishes and resuspended in DPBS medium and assayed for cell density using a Scepter automated cell counter (Millipore, #PHCC00000). The cells were diluted to a solution containing 44,000 cells per ml. The cell solution after the density adjustment was added to the cell assay plate at 90 μl per liter per well. The plates were placed in a 37 ° C, 5% CO ₂ incubator for 24 hours and then added with different concentrations of test compound. The cells were incubated with the compound for 72 hours in the presence of 10% fetal bovine serum. use

The Luminescent Cell Viability Assay kit (see manufacturer's instructions) was assayed for ATP content to assess cell growth inhibition. Briefly, add 30μl to each well.

The reagents were shaken for 10 minutes, cell lysis was induced, and fluorescence signals were recorded using a fluorescence/chemiluminescence analyzer Fluoroskan Ascent FL (Thermo Scientific Fluoroskan Ascent FL). The cells were treated with dimethyl sulfoxide (DMSO) for 72 hours to obtain the maximum signal value. The minimum signal value obtained from a separate medium (zero cell number) is defined as 0. Inhibition rate % = (maximum signal value - compound signal value) / (maximum signal value - minimum signal value) X 100%. Data was processed using GraphPad Prism V5.0 (GraphPad Software, San Diego, CA) software. IC50 values were calculated by sigmoidal dose-response curve fitting.

2. Experimental results

Table 1 lists the representative compounds 2, 3, and 5 described in the present invention, which have anti-cell proliferation against tumor cells SW620, MCF7, MDA-MD-231, LOVO, H1975, and Colon 205 in cell-based assays. The activity was compared with BBI608 (Shanghai Haiyan Yan Chemical Co., Ltd., batch number: 1512224) and compounds 1, 20 in the examples.

Table 1 Compound inhibition on tumor cell proliferation IC ₅₀ (nM)

Note: "--" means not detected.

The inhibitory activity of Compound 5 against MCF7 tumor cells was comparable to that of Compound 2.

The above results indicate:

The compound of the present invention has strong anti-tumor cell proliferation activity against various tumor cells.

The anti-tumor cell proliferation activity of the compounds of the invention is superior to the control BBI608.

The anti-tumor cell proliferation activity of the compounds of the present invention against various tumor cells is significantly superior to that of Compounds 1, 20.

Second, Western Blot (Western Blot) experiment

Experimental method

After SW480 colon cancer cells and K562 chronic myeloid leukemia cells were cultured in a 100 mm culture dish for 24 hours, test compound 1, compound 2, compound 3 or reference compound (STAT3 inhibitor BBI608 (Shanghai Haiyan Chemical Co., Ltd., batch number: 1512224), Jak inhibitor INCB018424 (ChemExpress, Cat. No. HY-50856) was cultured for 6, 12 or 24 hours, washed once with pre-cooled PBS, and collected in tubes, using cell extract (Invitrogen, Cat#FNN0011) The cells were lysed, the tubes were placed on ice for 30 minutes, centrifuged at 14,000 rpm for 30 min at 4 ° C, and the supernatant was taken and stored at -80 ° C.

The protein concentration was determined by Bradford method. 15 ug of protein was loaded from each sample. Protein was separated by SDS-PAGE electrophoresis (120 V) and transferred to PVDF membrane (40 min, 120 V) using Bio-Rad's Tran-Blot. The solution (25 g BSA per 100 ml TBST) was blocked for 120 min at room temperature, and the corresponding primary anti-Stat3 antibody (D3Z2G) (CST, #12640S), Phospho-Stat3 (Tyr705) antibody (CST, #9145S), Phospho-Stat2 (Ser727) were added. The antibody (CST, #9134S), GAPDH antibody (D16H11) (CST, #5174S) was incubated overnight at 4 ° C, and then the membrane was washed with TBST solution for 3 x 5 minutes. HRP-linked Anti-Rabbit lgG (CST#7074) Incubate for 45 minutes at room temperature in the dark and then wash the membrane with TBST for 3 x 5 minutes. Chemiluminescence scanning imaging was detected by placing the membrane on an imaging system (Cell Biosciences) using ECL Western Blotting Detection (Thermo, #34095).

2. Experimental results

From Fig. 1 ("INCB" is an abbreviation for INCB018424), Compound 1 and the STAT3 inhibitor BBI608 inhibited phospho-STAT3Ser727 in the SW480 colon cancer cell line. At the same time, Compound 1 and BBI608 reduced the level of phospho-STAT3Tyr705, which was more pronounced at high concentrations of 2 μM and 24 hours. At high concentrations and incubation times of 12-24 hours, total STAT3 levels were also down-regulated, and Compound 1 was more pronounced at 24 hours.

From Fig. 2 ("INCB" is an abbreviation for INCB018424), in K562 chronic myeloid leukemia cell line, compound 1 inhibits phospho-STAT3Ser727, while STAT3 inhibitor BBI608 has no significant effect on phospho-STAT3Ser727. Both did not significantly alter the phospho-STAT3Tyr705 level.

Under the conditions of this experiment, the Jak inhibitor INCB018424 did not affect the phosphorylation level of STAT3 in SW480 and K562 cells.

Figure 3-4 ("Veh" is a vehicle abbreviation) shows total STAT3, p-Stat3 (Tyr705) and p-Stat3 in SW480 cells and K562 cells treated with different concentrations of Compound 2, Compound 3, and BBI608 at different times. (Ber727) results of immunoblot analysis.

As shown in Figure 3-4, in the SW480 colon cancer cell line, Compound 2 and Compound 3 reduced the levels of phospho-STAT3Tyr705 and phospho-STAT3Ser727 after treatment, and the high concentration (2 μM) was significantly inhibited, which was stronger than the control compound BBI608. .

The decrease in total STAT3 and β-actin levels after treatment of compounds 2 and 3 at high concentrations for 24 hours may be associated with partial tumor cell death.

In K562 chronic myeloid leukemia cell line, compound 2 and compound 3 reduced phospho-STAT3Tyr705 levels after 6 hours and 24 hours of treatment, especially at high concentrations; under the same experimental conditions, the two compounds were treated at high concentrations. The phospho-STAT3Ser727 level was significantly reduced in 24 hours. Compounds 2 and 3 were more potent at the same concentration (2 μM) than the control compound BBI608, especially after 24 hours of treatment.

Example 9 Pharmacokinetic (PK) experiment

Experimental method

Male SD rats (Guangdong Provincial Medical Laboratory Animal Center) weighing 300-350 g were fasted overnight before the test. The test compound was dissolved in 30% sulfobutyl-β-cyclodextrin (SBE-β-CD) and administered orally at 20 mg/kg. Blood was taken at the end of the 15th, 30th, and 1st, 2nd, 3rd, 4th, 6th, 8th and 24th hours after administration. About 0.3ml was taken at each time point and placed in a centrifuge tube containing K2-EDTA. Plasma was taken by centrifugation (2,000 g, 10 minutes, 4 ° C) and stored in an ultra-low temperature freezer at -80 °C. 50 μL of the plasma sample was mixed with 5 μl of internal standard (IS) and extracted with ethyl acetate. The residue was redissolved in acetonitrile after drying in vacuo. The sample was filtered and injected into LC-MS/MS analysis.

2. Experimental results

The experimental results are shown in Table 4. In Table 4, T _max refers to the peak time, C _max refers to the maximum blood concentration, T _1/2 is the half life, AUC _last refers to the area under the time-concentration curve of 0-24 hours, and AUC _inf refers to 0-Inf Area under the time-concentration curve.

Table 4 results of pharmacokinetic experiments

As can be seen from Figures 5-6 and Table 4, the compound 2-3 of the present invention has a fast absorption rate and good absorption after gavage, and _Tmax is 0.58 hours and 0.42 hours, respectively; the half-lives are 12.02 hours and 8.58 hours, respectively.

Although specific embodiments of the invention have been described in detail, those skilled in the art will understand. Various modifications and alterations of the details are possible in light of the teachings of the invention. The full scope of the invention is given by the appended claims and any equivalents thereof.

Claims (18)

a compound of the formula (I), a prodrug thereof, a stereoisomer or a pharmaceutically acceptable salt,

among them, The A, B, D and E atoms are each independently selected from the group consisting of a C atom and an N atom, and one of A, B, D and E is an N atom; R _{1 is} selected from the group consisting of hydrogen, halogen, nitro, cyano, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, aryl and heteroaryl; wherein said C ₁ -C ₆ alkyl, The C ₁ -C ₆ alkoxy, aryl and heteroaryl are unsubstituted or substituted by one or more (for example 1, 2, 3 or 4) substituents selected from halogen, hydroxy, amino and Cyano group R ₂ is C ₁ -C ₆ alkyl or aryl; R ₃ is hydrogen or a C ₁ -C ₆ alkyl group. A compound, a prodrug, a stereoisomer or a pharmaceutically acceptable salt thereof, according to claim 1, wherein R _{1 is} selected from the group consisting of hydrogen, halogen, nitro, cyano, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, phenyl and 5-6 membered heteroaryl; wherein said C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, phenyl and 5-6 membered heteroaryl are unsubstituted or substituted by one or more (for example 1, 2, 3 or 4) substituents selected from Substituted: halogen, hydroxy, amino and cyano; Preferably, R _{1 is} selected from the group consisting of hydrogen, halogen, nitro, cyano, trifluoromethyl, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, phenyl, furan, thiophene, pyrrole, pyrimidine, Pyrazine, pyridazine and pyrimidine; More preferably, R _{1 is} selected from the group consisting of hydrogen, fluorine, chlorine, nitro, cyano, trifluoromethyl, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, methoxy, B. Oxyl, phenyl, furan and thiophene. The compound according to claim 1 or 2, a prodrug thereof, a stereoisomer or a pharmaceutically acceptable salt thereof, wherein R ₂ is a C ₁ -C ₄ alkyl group or a phenyl group; Preferably, R _{2 is} selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, isobutyl and phenyl. A compound, a prodrug, a stereoisomer or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 3, wherein R _{3 is} selected from hydrogen or C ₁ -C ₄ alkyl; Preferably, R ₃ is hydrogen or methyl. A compound, a prodrug, a stereoisomer or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 4, wherein the compound has the structure represented by the formula (II):

Wherein R ₁ , R ₂ , R ₃ are as defined in any one of claims 1-4. A compound, a prodrug, a stereoisomer or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 4, wherein the compound has the structure represented by the formula (III):

Wherein R ₁ , R ₂ , R ₃ are as defined in any one of claims 1-4. A compound, a prodrug, a stereoisomer or a pharmaceutically acceptable salt thereof, according to claim 5 or 6, wherein R ₁ is at the meta or para position of the N atom; Preferably, R _{1 is} selected from the group consisting of hydrogen, fluorine, chlorine, nitro, cyano, methyl, ethyl, isopropyl, methoxy, phenyl, furan and thiophene; More preferably, R ₁ is methyl or ethyl; Preferably, R _{2 is} selected from the group consisting of methyl, ethyl, isopropyl and phenyl; More preferably, R ₂ is a methyl group; Preferably, R ₃ is hydrogen or methyl; More preferably, R ₃ is hydrogen. A compound, a prodrug, a stereoisomer or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 4, wherein the compound has the structure represented by formula (IV) or formula (V):

Wherein R ₁ , R ₂ , R ₃ are as defined in any one of claims 1-4; Preferably, R ₁ is hydrogen; Preferably, R ₂ is a phenyl group; Preferably, R ₃ is hydrogen. A compound, a prodrug, a stereoisomer or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 4, wherein the compound has the structure represented by formula (VI) or formula (VII):

among them, R ₁ is a C ₁ -C ₆ alkyl group; R ₂ is C ₁ -C ₆ alkyl; Preferably, R ₁ is a C ₁ -C ₄ alkyl group; Preferably, R ₂ is a C ₁ -C ₄ alkyl group. A compound, a prodrug, a stereoisomer or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 9, wherein the compound is selected from the group consisting of:

A pharmaceutical composition comprising a compound according to any one of claims 1 to 10, a prodrug, a stereoisomer or a pharmaceutically acceptable salt thereof, and one or more pharmaceutical excipients. A compound according to any one of claims 1 to 10, a prodrug, a stereoisomer or a pharmaceutically acceptable salt thereof or Use of the pharmaceutical composition of claim 11 in the manufacture of a STAT3 inhibitor. Use of a compound according to any one of claims 1 to 10, a prodrug, a stereoisomer or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 11 for the preparation of a medicament for inhibiting proliferation of tumor cells; Preferably, the tumor cells are selected from the group consisting of colon cancer, breast cancer, colorectal cancer, and cancer cells of lung cancer. Use of a compound according to any one of claims 1 to 10, a prodrug, a stereoisomer or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 11 for the preparation of a medicament for the prevention and/or treatment of a tumor; Preferably, the tumor is selected from the group consisting of colon cancer, breast cancer, colorectal cancer, and lung cancer. A method of inhibiting proliferation of a tumor cell in vivo or in vitro, comprising administering to a subject in need thereof an effective amount of a compound according to any one of claims 1 to 10, a prodrug thereof, a stereoisomer or a pharmaceutically acceptable Salt or the pharmaceutical composition of claim 11; Preferably, the tumor cells are selected from the group consisting of colon cancer, breast cancer, colorectal cancer, and cancer cells of lung cancer. A method of preventing and/or treating a tumor comprising administering to a subject in need thereof an effective amount of a compound according to any one of claims 1 to 10, a prodrug, a stereoisomer or a pharmaceutically acceptable salt thereof or The pharmaceutical composition of claim 11; Preferably, the tumor is selected from the group consisting of colon cancer, breast cancer, colorectal cancer, and lung cancer. A compound according to any one of claims 1 to 10, a prodrug, a stereoisomer or a pharmaceutically acceptable salt thereof or a pharmaceutical composition according to claim 11 for use in inhibiting STAT3. A compound according to any one of claims 1 to 10, a prodrug, a stereoisomer or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 11 for inhibiting tumor cell proliferation or for preventing and/or treating Tumor Preferably, the tumor cells are selected from the group consisting of cancer cells of colon cancer, breast cancer, colon cancer and lung cancer; Preferably, the tumor is selected from the group consisting of colon cancer, breast cancer, colorectal cancer, and lung cancer.

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